U.S. patent number 5,107,016 [Application Number 07/460,236] was granted by the patent office on 1992-04-21 for process for the preparation of .beta.-hydroxybutyric acid esters.
This patent grant is currently assigned to Solvay & Cie (Societe Anonyme). Invention is credited to Pascal Pennetreau.
United States Patent |
5,107,016 |
Pennetreau |
April 21, 1992 |
Process for the preparation of .beta.-hydroxybutyric acid
esters
Abstract
Process for the preparation of .beta.-hydroxybutyric acid
esters, comprising: 1) a step involving alcoholysis of the
polyhydroxybutyrate in the presence of an alcohol, a halogenated
solvent, and an acid, 2) a neutralization step comprising the
addition of an alcoholate in solution in the alcohol, 3) a
purification step comprising the addition of a halogenated solvent
and the azeotropic removal of water and the alcohol, 4) a step for
recovery of the ester, comprising a filtration, a distillation of
the halogenated solvent and a distillation of the ester. This
process enables .beta.-hydroxybutyric acid esters of high purity to
be obtained.
Inventors: |
Pennetreau; Pascal (La Hulpe,
BE) |
Assignee: |
Solvay & Cie (Societe
Anonyme) (Brussels, BE)
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Family
ID: |
9377603 |
Appl.
No.: |
07/460,236 |
Filed: |
January 2, 1990 |
Foreign Application Priority Data
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Jan 6, 1989 [FR] |
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89 00243 |
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Current U.S.
Class: |
560/179 |
Current CPC
Class: |
C07C
69/675 (20130101); C12P 7/62 (20130101); C07C
67/03 (20130101) |
Current International
Class: |
C12P
7/62 (20060101); C07C 67/03 (20060101); C07C
67/00 (20060101); C07C 69/00 (20060101); C07C
69/675 (20060101); C07C 069/66 () |
Field of
Search: |
;560/179 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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0046017 |
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Feb 1982 |
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EP |
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2822472 |
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Dec 1978 |
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DE |
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2369242 |
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May 1978 |
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FR |
|
Other References
"Helvetica Chimica Acta", vol. 65, No. 49, 1982, pp. 495-503. .
The Merck Index, Tenth Edition, pp. 1230 and 1232, published by
Merck & Co., Inc., (1983)..
|
Primary Examiner: Gray; Bruce
Attorney, Agent or Firm: Spencer & Frank
Claims
I claim:
1. Process for the preparation of .beta.-hydroxybutyric acid esters
from poly-.beta.-hydroxybutyrate, characterized in that this
process comprises:
a) a first step in which an alcoholysis of the
poly-.beta.-hydroxybutyrate is carried out in a medium comprising a
homogeneous liquid phase of an alcohol, a halogenated solvent and
an acid,
b) a second step in which the acid is neutralized with a alcoholate
soluble in the homogeneous liquid phase,
c) a third step in which a halogenated solvent is added to the
medium and the water formed and the alcohol are removed by
azeotropic distillation, and
d) a fourth step in which the ester is recovered.
2. Process according to claim 1, characterized in that the
alcoholate corresponds to the alcohol used in the first step.
3. Process according to claim 1 characterized in that the
alcoholate is used in solution in the alcohol used in the first
step.
4. Process according to any one of the preceding claim 1
characterized in that the fourth step comprises filtration and/or
centrifugation.
5. Process according to claim 4, characterized in that the fourth
step comprises a distillation of the ester.
6. Process according to claim 1 characterized in that the
halogenated solvent used in the first step and in the third step is
chosen, independently of one another, from the chloromethanes, the
chloroethanes and the chloropropanes.
7. Process according to claim 6, characterized in that the
halogenated solvent used in the first step and the halogenated
solvent used in the third step are identical.
8. Process according to claim 7, characterized in that the
halogenated solvent is 1,2-dichloropropane.
Description
The present invention relates to a process for the preparation of
.beta.-hydroxybutyric acid esters by alcoholysis of
poly-.beta.-hydroxybutyrate.
A process for the preparation of .beta.-hydroxybutyric acid esters
has already been proposed in the document Helvetica Chim Acta 1982,
65 (2), p. 495-503. This process comprises a step involving
alcoholysis of poly-hydroxybutyrate, which may or may not be
isolated from the biomass, with the aid of methanol and sulphuric
acid in the presence of a solvent such as 1,2-dichloroethane, a
neutralization step by washings with an aqueous solution of NaCl
and an aqueous solution of NaHCO.sub.3 and then a purification step
comprising drying over magnesium sulphate, filtration under reduced
pressure and distillation. The washing steps in such a process lead
to mixtures which are not easy to separate by settling, in
particular because of the presence of two phases, an aqueous phase
and an organic phase, which leads to the formation of emulsions
Moreover, the reaction time, the separation time and the settling
time are very long.
The aim of the present invention is to provide a process which does
not have the drawbacks of this prior process.
To this end, the present invention relates to a process for the
preparation of .beta.-hydroxybutyric acid esters from
poly-.beta.-hydroxybutyrate, comprising:
a) a first step in which an alcoholysis of the
poly-.beta.-hydroxybutyrate is carried out in a medium comprising a
homogeneous liquid phase of an alcohol, a halogenated solvent and
an acid,
b) a second step in which the acid is neutralized with a base
soluble in the homogeneous liquid phase,
c) a third step in which a halogenated solvent is added to the
medium and the water formed and the alcohol are removed by
azeotropic distillation, and
d) a fourth step in which the ester formed is recovered.
The poly-.beta.-hydroxybutyrate which can be treated according to
the invention can be obtained in various ways. Numerous
microorganisms, in particular bacteria, are capable of synthesizing
it. The selection of the microorganisms is in general made on the
basis of the relative amount of poly-.beta.-hydroxybutyrate
contained in the microorganism and as a function of the speed of
growth of the microorganism and its rate of synthesis of
poly-.beta.-hydroxybutyrate.
These microorganisms can be treated directly, after separation and
subsequent drying of the culture medium, to effect the alcoholysis
of the poly-.beta.-hydroxybutyrate without prior extraction of the
poly-.beta.-hydroxybutyrate. This separation can be effected by all
means known to this end. One method of proceeding consists in
centrifuging the culture medium so as to separate the
microorganisms from the medium, washing the microganisms with water
and subsequently drying the microorganisms.
Another technique, described in European Patent 0,168,095, consists
in extracting the poly-.beta.-hydroxybutyrate from an aqueous
suspension of microorganisms using a solvent which forms an
azeotrope at least with the water, the water being removed by an
azeotropic route.
Another technique consists in treating the microorganisms with a
solution of sodium hypochlorite in order to obtain a
poly-.beta.-hydroxybutyrate which no longer contains cellular
debris and in then drying the product obtained.
The alcohol used in the first step is chosen according to the type
of ester which it is desired to prepare. Any type of alcohol may be
used in the process according to the invention. In general, the
process is carried out using aliphatic alcohols containing from 1
to 4 carbon atoms and more particularly using methanol, ethanol and
propanol. Finally, good results have been obtained, in particular,
with methanol and ethanol.
When methanol is used in the process, 0.1 to 50 ml of alcohol per g
of poly-.beta.-hydroxybutyrate is customarily used. Preferably,
from 0.5 to 20 ml of alcohol per g of poly-.beta.-hydroxybutyrate
is used.
The halogenated solvents for the poly-.beta.-hydroxybutyrate which
are used in the first step are chosen from the solvents for
poly-.beta.-hydroxybutyrate which are miscible with alcohol and can
be separated from the ester by distillation. Customarily,
chloromethanes, chloroethanes and chloropropanes are used. In
general, chloroform, 1,2-dichloroethane, 1,2-dichloropropane,
1,1,2,-trichloroethane, 1,1,2,2-tetrachloroethane and
1,2,3-trichloropropane are used. Preferably, however,
1,2-dichloropropane or 1,2-dichloroethane is used. Finally, the
solvent very particularly preferred is 1,2-dichloropropane.
When 1,2-dichloropropane is used as the halogenated solvent in the
process of the invention, from 0.1 to 50 ml of 1,2-dichloropropane
per g of poly-.beta.-hydroxybutyrate, and preferably from 1 to 20
ml of 1,2-dichloropropane per g of poly-.beta.-hydroxybutyrate, is
used.
The acids used in the first step are those currently used in the
prior art as an esterification catalyst. Sulphuric acid,
p-toluenesulphonic acid and methanesulphonic acid are customarily
used. Amongst these, good results have been obtained with sulphuric
acid.
When sulphuric acid is used, amounts of between 1 and 5% by volume
of concentrated acid in the alcohol, preferably from 2 to 4%, are
customarily used.
In the process according to the invention, the reaction is carried
out in a reaction mixture where the solvent, the alcohol, the acid
and poly-.beta.-hydroxybutyrate constitute only a single
homogeneous liquid phase; the reaction mixture can, however,
contain cellular debris and possibly undissolved
poly-.beta.-hydroxybutyrate, but whatever the case the reaction is
carried out in the absence of a second liquid phase.
The temperature at which the first step of the process is carried
out is between 25.degree. and 160.degree. C. It is preferably
between 35.degree. and 150.degree. C.; good results have been
obtained between 50.degree. and 140.degree. C.
The pressure at which the first step of the process is carried out
is generally between 1 and 10 bars; it is customarily between 3 and
8 bars. Preferably, the reaction is carried out under autogenous
pressure, which implies that the working pressure is fixed by the
composition of the reaction mixture and by the temperature
chosen.
The first step of the process according to the invention can be
carried out in any equipment designed for this purpose.
During the second step of the process according to the invention,
the acid is neutralized with a base which is a soluble in the
homogeneous liquid phase and which forms with the acid a salt which
precipitates at least partially from the mixture. Customarily an
alkali metal alcoholate or alkaline earth metal alcoholate is used.
Preferably, the alcoholate corresponding to the alcohol used in the
first step is employed and sodium or potassium is used as the
alkali metal or alkaline earth metal.
The addition of the base can be discontinuous. The neutralization
is monitored by following the change in the mixture as a function
of the coloration of a pH paper; the addition of base is stopped
when the coloration of a pH paper corresponds to an acidity of
between pH 5 and 6 in the aqueous phase.
Preferably, the base is used in solution in the same alcohol as
that used in the first step.
The temperature at which the second step of the process is carried
out is customarily between 20.degree. and 50.degree. C. and good
results have been obtained at ambient temperature.
The pressure at which the second step of the process is carried out
is between 1 and 3 bars: good results have been obtained at
atmospheric pressure.
The second step of the process according to the invention can be
carried out in any equipment designed for this purpose. Usually it
is carried out in the equipment of the first step.
During the third step, a halogenated solvent is added to the
mixture in order to remove the water formed, and in particular the
alcohol, by azeotropic distillation.
The customary solvents for poly-.beta.-hydroxybutyrate can be used
as the halogenated solvent. In general, the chloromethanes,
chloroethanes or chloropropanes are used, such as chloroform,
1,2-dichloroethane, 1,2-dichloropropane, 1,1,2,-trichloroethane,
1,1,2,2-tetrachloroethane and 1,2,3-trichloropropane. Preferably, a
halogenated solvent identical to that used in the first step is
employed. Accordingly, 1,2-dichloropropane is particularly
preferably used in this step.
To effect the azeotropic removal, a volume of halogenated solvent
equal to the expected volume of azeotrope is added to the mixture;
this addition can be effected continuously before or during the
distillation operation.
The azeotrope is removed under atmospheric pressure or under
reduced pressure. The removal of the solvent is stopped when the
temperature at the top reaches the boiling temperature of the pure
solvent.
During the fourth step, the ester is recovered without further
difficulty by any known technique, such as, in particular,
filtration and/or centrifugation, followed by washing preferably
carried out with a halogenated solvent identical to that used
during the first or the third step, followed by a distillation of
the halogenated solvent and a distillation of the
.beta.-hydroxybutyric acid ester.
The .beta.-hydroxybutyric acid ester obtained by the process of the
invention can be used in all the applications known for this
product, that is to say in particular as a medicament, as an
intermediate in the fine chemicals industry or as an additive in
animal feeds.
The .beta.-hydroxybutyric acid ester obtained according to the
process of the invention can be used as such in chemical synthesis
or can be hydrolysed with a view to obtaining .beta.-hydroxybutyric
acid with a minimum formation of crotonic acid.
The example which follows serves to illustrate the invention.
EXAMPLE 1
200 ml of 1,2-dichloropropane, 200 ml of methanol, 6 ml of
concentrated sulphuric acid (0.110 mole of H.sub.2 SO.sub.4) and 72
g of a culture of microorganisms which has been centrifuged, washed
and then dried and which contains 60% of
poly-.beta.-hydroxybutyrate, which corresponds to 0.5 mole of
C.sub.4 units, are introduced, with stirring, into a 1-litre
autoclave fitted with a manometer, a system for heating and
controlling the temperature, a stirrer and a tube enabling samples
to be taken.
The reactor is purged with nitrogen and the mixture is then heated
at 110.degree. C. for 5 hours. The pressure rises from 4.75 to 5
bars.
Heating is stopped and the reaction mixture is allowed to return to
ambient temperature.
45 ml of a 1.3 M methanolic solution of sodium methylate are then
added to the mixture; this addition neutralizes the sulphuric
acid.
355 ml of 1,2-dichloropropane are then added to the mixture and
azeotropic removal is carried out under atmospheric pressure; the
boiling point of the azeotrope is 63.degree. C.
The removal of 1,2-dichloropropane is stopped when the temperature
reaches 96.degree. C., the boiling point of
1,2-dichloropropane.
The mixture is then filtered through a frit plate of porosity P3 in
2 minutes and the residue is washed twice with 200 ml of
1,2-dichloropropane.
The filter cake is then dried under reduced pressure (<10 mm Hg)
to constant weight. The filter cake has a moist weight of about 110
g and a final weight of about 45 g.
The 1,2-dichloropropane is removed under reduced pressure (<10
mm Hg) and the .beta.-hydroxybutyric acid ester is then distilled
under a pressure of 20 mm Hg. The boiling point of the methyl ester
is 76.degree. C. under 20 mm Hg.
50 g of virtually pure methyl .beta.-hydroxybutyrate are
obtained.
The ester contains very little methyl crotonate, of the order of
0.05 to 0.1 g/kg.
The distillation yields are 90%.
The 1,2-dichloropropane recovered during the distillation and
washing operations is recycled in the process.
* * * * *